Liver Tumor-promoting Activity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant Rat Strains
2000
Risk
assessment of dioxins is currently based on induction of liver tumors
in rats. The toxicity of dioxins is characterized by large sensitivity
differences among animal species and even strains of the same species,
which complicates the risk assessment. The significance of these
differences in dioxin-induced carcinogenicity is not known. We
therefore studied the liver tumor-promoting activity of
2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) in the
sensitive Long-Evans (L-E) and the resistant Han/Wistar (H/W) rats
differing >1000-fold in their sensitivity to the acute lethality of
TCDD. Female rats were partially hepatectomized, initiated with
nitrosodiethylamine, and treated with TCDD for 20 weeks. Altered
hepatic foci (AHF) were stereologically quantitated using glutathione
S -transferase P as a marker. AHF were significantly
( P < 0.001) and dose dependently
increased in L-E rats at 10 and 100 ng/kg/day, but in H/W rats only at
1000 ng/kg/day and above, indicating a remarkable (∼100-fold)
sensitivity difference between L-E and H/W rats. The same sensitivity
difference but 10-fold less foci were observed between
nonhepatectomized/noninitiated L-E and H/W rats. Induction of AHF was
related to hepatotoxicity but not to cytochrome P4501A1 activity in the
liver. Liver TCDD concentrations were similar in both strains. H/W rats
are exceptionally resistant to induction of AHF by TCDD, and the
resistance is associated with an altered transactivation domain of the
aryl hydrocarbon receptor. Genetic differences may account for
significant interindividual/intraspecies sensitivity differences in
dioxin-induced carcinogenesis. Understanding the role of
transactivation domain of the aryl hydrocarbon receptor in
carcinogenesis is therefore likely to improve dioxin risk assessment.
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